Our goal is to understand the molecular bases for the control of body weight by using molecular genetic and molecular physiological approaches in humans and rodents. There is growing evidence that multiple genes - each with relatively modest effect on relevant phenotypes such as food intake, energy expenditure, hedonic responses to food - interact with each other, intrauterine and early neonatal development, and the environment, to determine an individual's susceptibility to become obese within a specific environment. Deployment of reciprocal molecular genetic approaches in humans and mice provides a powerful platform by which to identify and characterize these genes. The feasibility of genome-wide association studies (GWAS) utilizing large numbers of subjects (ultimately >100,000), availability of low cost/high throughput sequencing techniques, and access to sophisticated computational approaches, will create a deluge of genes with strong statistical but virtually no physiological insight into the mechanism(s) of action with regard to obesity. Mice - that can be manipulated and studied with a wide repertoire of transgenic, neurophysiologic and bioenergetic techniques - are an optimal resource for delineating the mechanism of action of such genes. We have used these approaches fruitfully in the past, and propose to continue to do so. This proposal has 2 major Aims: 1. To identify new genes mediating the control of body weight in humans;2. To identify the molecular bases for the effects of these genes. Aim 1 will make use of our access to large collections of human subjects (New York Health Project, Yup'ik Eskimos, DNA samples selected from extremes of BMI in the NHANES, and the international GIANT consortium);a prospective study of the effects on body weight with use of second generation antipsychotic medications;and individuals with syndromic and severe, early onset obesities. Using a range of strategies, we will identify new genes for human obesity. Aim 2 will use mice to address the molecular physiology of a recently discovered pair of adjacent genes (FTO/FTM) - and a related transcription factor, CUTL1 - strongly implicated in obesity by three GWAS;and a gene (MGRN1=mahoganoid) recently cloned by us and another group which acts in the MC4R signaling pathway by unknown mechanisms. This Aim will also provide for creation and study of transgenic animals segregating for "designer" alleles of genes identified in the first specific aim. PUBLIC HEALTH RELEVANCE: Obesity is arguably the major health issue - in terms of medical morbidity and costs - now confronting developed and developing nations. Body weight and degree of fatness (adiposity) reflect the interactions of an individual's genes with developmental and environmental factors. This grant is designed to identify the genes responsible for susceptibility to obesity in humans. Success in this endeavor will impact diagnosis, treatment and prevention of obesity and its associated co-morbidities such as diabetes and heart disease.